Met Proto-Oncogene and Insulin-Like Growth Factor Binding Protein 3 Overexpression Correlates with Metastatic Ability in Well-Differentiated Pancreatic Endocrine Neoplasms

Hansel, Donna E.; Rahman, Asifur; House, Michael G.; Ashfaq, Raheela; Berg, Karin D.; Yeo, Charles J.; Maitra, Anirban

doi:10.1158/1078-0432.ccr-04-0285

Cited by 142 publications

(111 citation statements)

References 29 publications

(27 reference statements)

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“…Previous studies compared WDETs with normal islet controls (Maitra et al 2003), MEN-1 associated NETs with normal islets (Dilley et al 2005), PNETs with normal pancreas, pancreatitis, and pancreatic adenocarcinoma (Bloomston et al 2004), non-functioning PNETs and their metastases with normal islets (Capurso et al 2006), and metastatic with non-metastatic PNETs, primarily nonfunctioning (Hansel et al 2004, Couvelard et al 2006. Interestingly, there was no significant overlap between the identified genes in these studies and our current analysis.…”

Section: E-m Duerr Et Al: Gene Expression In Netssupporting

confidence: 43%

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

Duerr

Mizukami²,

Ng³

et al. 2008

Endocrine Related Cancer

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Current classifications of human gastroenteropancreatic neuroendocrine tumors (NETs) are inconsistent and based upon histopathologic but not molecular features. We sought to compare a molecular classification with the World Health Organization (WHO) histologic classification, identify genes that may be important for tumor progression, and determine whether gastrointestinal NETs (GI-NETs) differ in their molecular profile from pancreatic NETs (PNETs). DNA microarray analysis was performed to identify differentially expressed genes in PNETs and GI-NETs. Confirmation of expression levels was obtained by quantitative real-time PCR. Immunoblotting and mutational analysis were performed for selected genes. Hierarchical clustering of 19 PNETs revealed a 'benign' and 'malignant' cluster that corresponded well with the WHO categories of welldifferentiated endocrine tumor (WDET) and well-differentiated endocrine carcinoma (WDEC) respectively. FEV, adenylate cyclase 2 (ADCY2), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and growth arrest and DNA-damage-inducible, beta (GADD45b) were the most highly up-regulated genes in the malignant group of PNETs. Platelet-derived growth factor receptor (PDGFR) was expressed in both WDETs and WDECs, and phosphorylation of PDGFR-b was observed in 83% of all PNETs. Malignant ileal GI-NETs exhibited a distinctive gene expression profile, and extracellular matrix protein 1 (ECM), vesicular monoamine member 1 (VMAT1), galectin 4 (LGALS4), and RET Proto-oncogene (RET) were highly up-regulated genes. Gene expression profiles reflect the current WHO classification and can distinguish benign from malignant PNETs and also PNETs from GI-NETs. This suggests that molecular profiling may enhance tumor classification schemes. Potential gene targets have also been identified, and PDGFR and RET are candidates that may represent novel therapeutic targets.

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Section: E-m Duerr Et Al: Gene Expression In Netssupporting

confidence: 43%

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

Duerr

Mizukami²,

Ng³

et al. 2008

Endocrine Related Cancer

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“…Nevertheless, MET proto-oncogene over-expression has been correlated with metastatic ability in well-differentiated PNETs (Hansel et al 2004), and further investigation in a larger cohort of SBNETs is warranted. We also noticed that miR-1 targets VEGFA, and found VEGFA levels are indeed significantly higher in LN and liver metastases compared with primary SBNETs (Supplementary Fig.…”

Section: :9mentioning

confidence: 99%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

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Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.

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“…FFPE sections of syngeneic pairs of human normal and tumor tissues (Cureline Inc.) were deparaffinized, rehydrated, and subjected to antigen retrieval as it was previously described. 40 PARP1 was detected with goat anti-PARP1 primary antibody (SC-156, Santa Cruz Biotechnology Inc., Santa Cruz, CA) as per the manufacturer's instructions, using FFPE normal human spleen samples (Cureline BioPathology) as a positive control. ER status in human breast carcinomas was detected with monoclonal mouse antihuman estrogen receptor α antibody, clone 1D5 (1:35; Dako, Glostrup, Denmark), and PR status was detected with mouse monoclonal antihuman PR antibody, clone PgR 636 (Dako), as per the manufacturer's instructions, using FFPE breast carcinoma (Cureline BioPathology) as a positive control.…”

Section: Qrt-pcr-based Transcriptional Profiling Of Gene Expression Imentioning

confidence: 99%

Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types

et al. 2010

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IntroductionPoly (ADP-ribose) polymerase-1 (PARP1) is a chromatinassociated enzyme with key functions in the regulation of transcription, cell cycle, tumorigenesis, and cellular response to DNA damage. 1 PARP1 is activated by DNA damage and has important roles in DNA base excision repair (BER), functioning as a nick sensor, recruiter, and modulator of key DNA repair molecules.2 Upon activation, PARP1 synthesizes poly (ADP-ribose) (PAR) using nicotinamide adenine dinucleotide (NAD + ) as a substrate and covalently transfers PAR to nuclear proteins, including nucleosomal core histones, topoisomerases I and II, high mobility group (HMG) proteins, and p53. 3 Loss of PARP1 activity can lead to enhanced cancer cell death, following treatment with PARP inhibitors, both as single agents and in combination with DNA-damaging agents. Impairing PARP1-dependent BER can elicit DNA double-strand breaks (DSBs) following collapse of the replication fork, particularly in cells whose homologous recombination (HR)-dependent DSB repair is already defective due to mutations in breast cancer 1 and 2 genes (BRCA1 and BRCA2); these defects are found frequently in familial breast and ovarian cancers and can elicit profound sensitization to PARP inhibitors, resulting in cytotoxic effects. 4,5 Over 80% of BRCA-associated breast cancers are negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). 6,7 These "triple-negative" breast cancers, which comprise 15% to 20% of all breast cancers, 8,9 are among the most aggressive breast cancer subtypes. Importantly, over 60% AbstractPoly (ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair and is implicated in pathways of tumorigenesis. PARP inhibitors have gained recent attention as rationally designed therapeutics for the treatment of several malignancies, particularly those associated with dysfunctional DNA repair pathways, including triple-negative breast cancer (TNBC). We investigated the PARP1 gene expression profile in surgical samples from more than 8,000 primary malignant and normal human tissues. PARP1 expression was found to be significantly increased in several malignant tissues, including those isolated from patients with breast, uterine, lung, ovarian, and skin cancers, and non-Hodgkin's lymphoma. Within breast infiltrating ductal carcinoma (IDC) samples tested, mean PARP1 expression was significantly higher relative to normal breast tissue, with over 30% of IDC samples demonstrating upregulation of PARP1, compared with 2.9% of normal tissues. Because of known DNA repair defects, including BRCA1 dysfunction, associated with TNBC, exploration of PARP1 expression in breast cancers related to expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) led to the observation that negative expression of any of the 3 receptors was associated with upregulation of PARP1 expression, compared with receptor-positive tissues. To validate these observations, an indep...

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Met Proto-Oncogene and Insulin-Like Growth Factor Binding Protein 3 Overexpression Correlates with Metastatic Ability in Well-Differentiated Pancreatic Endocrine Neoplasms

Cited by 142 publications

References 29 publications

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types

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